CLINICAL PHARMACOLOGY
Carvedilol is a racemic mixture in which nonselectiveβ-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.
Pharmacokinetics
Absorption
Carvedilol is rapidly and extensively absorbed following oral administration of conventional carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. The relative bioavailability (area under the curve [AUC], Cmax, trough concentration) of carvedilol as COREG CR is equivalent to the conventional carvedilol tablet when both are administered with food. The absorption of carvedilol from COREG CR is slower and more prolonged compared to the conventional carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of COREG CR 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for COREG CR and the conventional carvedilol tablet.
Effect of Food
Administration of COREG CR with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared to COREG CR administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when COREG CR was administered in the fasted state compared to administration after a standard meal. COREG CR should be taken with food.
In a study with adult subjects, sprinkling the contents of the COREG CR capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared to administration of the intact capsule following a standard meal but did result in a decrease in Cmax (18%).
Distribution
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues.
Metabolism and Excretion
Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.
Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration of COREG CR in healthy subjects. Plasma clearance ranges from 500 to 700 mL/min. The mean apparent terminal elimination half-life of carvedilol following administration of COREG CR is approximately 11 hours.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
Heart Failure
Following administration of conventional carvedilol tablets, steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in patients with heart failure. Compared to healthy subjects, heart failure patients had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.
The steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of COREG CR to chronic heart failure patients (mild, moderate, and severe) were equivalent to those observed after administration of conventional carvedilol tablets.
Hypertension
The pharmacokinetics (AUC, Cmax and trough concentrations) observed with administration of COREG CR were equivalent to those observed with conventional carvedilol tablets following repeat dosing in patients with essential hypertension.
Pharmacokinetic Drug-Drug Interactions
Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes.
The following drug interaction studies were performed with the conventional carvedilol tablet.
Rifampin
In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70%.
Cimetidine
In a pharmacokinetic study conducted in 10 healthy male subjects, cimetidine (1,000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change in Cmax.
Glyburide
In 12 healthy subjects, combined administration of carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound.
Hydrochlorothiazide
A single oral dose of carvedilol 25 mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.
Digoxin
Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 hypertensive patients.
Torsemide
In a study of 12 healthy subjects, combined oral administration of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone.
Warfarin
Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.
Special Populations
Elderly
Plasma levels of carvedilol average about 50% higher in the elderly compared to young subjects after administration of the conventional carvedilol tablet.
Hepatic Impairment
No studies have been performed with COREG CR in patients with hepatic impairment. Compared to healthy subjects, patients with cirrhotic liver disease exhibit significantly higher concentrations of carvedilol (approximately 4- to 7-fold) following single-dose therapy with the conventional carvedilol tablet.
Renal Insufficiency
No studies have been performed with COREG CR in patients with renal insufficiency. Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment after dosing with the conventional carvedilol tablet. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive patients with moderate to severe renal impairment compared to a control group of hypertensive patients with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in patients with impaired renal function.
Consistent with its high degree of plasma protein binding, carvedilol does not appear to be cleared significantly by hemodialysis.
Pharmacodynamics
Heart Failure and Left Ventricular Dysfunction Following Myocardial Infarction
The basis for the beneficial effects of COREG CR in heart failure and patients with left ventricular dysfunction following an acute myocardial infarction is not established. The β1-blocking effect (change in exercise-induced heart rate) of carvedilol was predicted in heart failure patients and patients with left ventricular dysfunction following myocardial infarction using a PK/PD model developed in healthy volunteers and steady-state S(-)-carvedilol concentration-time data obtained in these patients after administration of conventional carvedilol tablets (3.125, 6.25, 12.5, or 25 mg twice daily) and the equivalent dose of COREG CR (10, 20, 40, or 80 mg once daily). COREG CR had an equivalent predicted overall pharmacodynamic effect (area under the effect curve) and equivalent predicted minimum pharmacodynamic effect (PDmin) compared to conventional carvedilol tablets.
Hypertension
The mechanism by which β-blockade produces an antihypertensive effect has not been established.
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.
Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the conventional carvedilol tablet is administered with food at the recommended starting dose and titration increments are closely followed (see DOSAGE AND ADMINISTRATION).
In a randomized, double-blind, placebo-controlled trial, theβ1 blocking effect of COREG CR, as measured by heart rate response to submaximal bicycle ergometry, was shown to be equivalent to that observed with the conventional carvedilol tablet at steady state in adult patients with essential hypertension.
In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.
Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.
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CLINICAL TRIALS
Support for the use of COREG CR for the treatment of mild to severe heart failure and for patients with left ventricular dysfunction following myocardial infarction is based on the equivalence of pharmacokinetic and pharmacodynamic parameters between COREG CR and conventional carvedilol tablets (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Pharmacodynamics)
The clinical trials performed with conventional carvedilol tablets in heart failure and left ventricular dysfunction following myocardial infarction are presented below.
Heart Failure
A total of 6,975 patients with mild to severe heart failure were evaluated in placebo-controlled and active-controlled studies of carvedilol.
Trials in Mild-to-Moderate Heart Failure
Carvedilol was studied in 5 multicenter, placebo-controlled studies, and in 1 active-controlled study (COMET study) involving patients with mild-to-moderate heart failure.
Four US multicenter, double-blind, placebo-controlled studies enrolled 1,094 patients (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction≤0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were assigned to the studies based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled study enrolled 415 patients (half randomized to carvedilol) with less severe heart failure. All protocols excluded patients expected to undergo cardiac transplantation during the 7.5 to 15 months of double-blind follow-up. All randomized patients had tolerated a 2-week course on carvedilol 6.25 mg twice daily.
In each study, there was a primary end point, either progression of heart failure (1 US study) or exercise tolerance (2 US studies meeting enrollment goals and the Australia-New Zealand study). There were many secondary end points specified in these studies, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.
The results of the US and Australia-New Zealand trials were as follows:
Slowing Progression of Heart Failure
One US multicenter study (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow-up of 7 months, by 48% (p = 0.008).
In the Australia-New Zealand study, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US studies, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 studies. The Australia-New Zealand results were statistically borderline.
Functional Measures
None of the multicenter studies had NYHA classification as a primary end point, but all such studies had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all studies. Exercise tolerance was the primary end point in 3 studies; in none was a statistically significant effect found.
Subjective Measures
Quality of life, as measured with a standard questionnaire (a primary end point in 1 study), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most studies.
Mortality
Death was not a pre-specified end point in any study, but was analyzed in all studies. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 studies.
The COMET Trial
In this double-blind trial, 3,029 patients with NYHA class II-IV heart failure (left ventricular ejection fraction≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of the patients was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the patients had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.
The study had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. All-cause mortality carried most of the statistical weight and was the primary determinant of the study size. All-cause mortality was 34% in the patients treated with carvedilol and was 40% in the immediate-release metoprolol group (p = 0.0017; hazard ratio = 0.83, 95%CI 0.74-0.93). The difference between the 2 groups with respect to the composite end point was not significant (p = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.
It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (Toprol XL) with benefits in heart failure.
Trials in Severe Heart Failure
In a double-blind study (COPERNICUS), 2,289 patients with heart failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The study was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or congestive heart failure [CHF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI 0.52 − 0.81, p = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 1.
Table 1. Results of COPERNICUS |
End point
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Placebo N = 1,133
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Carvedilol N = 1,156
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Hazard ratio (95% CI)
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% Reduction
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Nominal p value
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Mortality
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190
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130
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0.65
(0.52 − 0.81)
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35
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0.00013
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Mortality + all hospitalization
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507
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425
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0.76
(0.67 − 0.87)
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24
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0.00004
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Mortality + CV hospitalization
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395
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314
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0.73
(0.63 − 0.84)
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27
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0.00002
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Mortality + CHF hospitalization
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357
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271
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0.69
(0.59 − 0.81)
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31
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0.000004
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The effect on mortality was principally the result of a reduction in the rate of sudden death among patients without worsening heart failure.Patients' global assessments, in which carvedilol-treated patients were compared to placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared to baseline. Patients treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.The protocol also specified that hospitalizations would be assessed. Fewer patients on carvedilol than on placebo were hospitalized for any reason (372 vs. 432, p = 0.0029), for cardiovascular reasons (246 vs. 314, p = 0.0003), or for worsening heart failure (198 vs. 268, p = 0.0001).Carvedilol had a consistent and beneficial effect on all-cause mortality as well as the combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall study population and in all subgroups examined, including men and women, elderly and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).
 Figure 2. Effects on Mortality for Subgroups in COPERNICUS
Left Ventricular Dysfunction Following Myocardial Infarction
CAPRICORN was a double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2% to 40%, p = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another study end point, total mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.
 Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)
 Figure 4. Effects on Mortality for Subgroups in CAPRICORN
Hypertension
A double-blind, placebo-controlled, 8-week trial evaluated the effects of COREG CR 20 mg, 40 mg, and 80 mg once daily in patients with essential hypertension (sitting diastolic blood pressure [DBP]≥ 90 and ≤ 109 mmHg). Dose titration occurred at 2-week intervals. The mean age of the patients was approximately 53 years, 66% were male, and the mean sitting systolic blood pressure (SBP) and DBP at baseline were 150 mmHg and 99 mmHg, respectively.
Clinically and statistically significant reductions in blood pressure as measured by 24-hour ambulatory blood pressure monitoring (ABPM) were observed with 20 mg, 40 mg, and 80 mg of COREG CR (see Figure 5). Mean changes from baseline in mean DBP were -4.4 mmHg, -7.9 mmHg, and -9.6 mmHg for COREG CR 20 mg, 40 mg, 80 mg, respectively, and -0.4 mmHg for placebo. Mean changes from baseline in mean SBP were -6.8 mmHg, -10.1 mmHg, -12.5 mmHg for COREG CR 20 mg, 40 mg, and 80 mg, respectively, and -0.6 mmHg for placebo. A statistically significant reduction from baseline in both SBP and DBP was maintained over the entire 24-hour period for all doses of COREG CR. The trough to peak ratio was 0.6 for COREG CR and -1.2 for placebo.
Carvedilol administered as the conventional tablets was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough-to-peak blood pressure showed a trough-to-peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers, responses were smaller in black than non-black patients. There were no age- or gender-related differences in response. The dose-related blood pressure response was accompanied by a dose-related increase in adverse effects (see ADVERSE REACTIONS).
Figure 5. Mean Blood Pressure Changes from Baseline Measured by 24 Hour ABPM
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